DESCRIPTION: (provided by the applicant) Drug abuse is a modern day plague that disrupts and destroys the lives of millions of people around the world. While preclinical research efforts have delineated key neurobiological components of the rewarding effects produced by stimulant drugs, the factors that contribute to relapse are not clearly defined. The withdrawal syndrome that follows repeated cocaine use includes drug craving, anxiety, and dysphoria. Recent clinical evidence demonstrates that cocaine addicts who exhibit depression during withdrawal display increased responsiveness to acute cocaine exposure and may therefore be at increased risk to relapse. One means to investigate the neurobiological and behavioral sequelae that may underlie this phenomenon is to develop an appropriate animal model. High DPAT Sensitive (HDS) rats, specially bred for enhanced sensitivity to the serotonin type-lA (5-HT1A) agonist 8-OH-DPAT, have proven valuable for the study of depression and this proposal predicts that HDS rats will be useful to study interactions between a genetic predisposition to depression and liability to relapse to cocaine within the same animal. The principle objective is to determine whether the depressive state exhibited by HDS rats increases the rate of relapse to cocaine self-administration during withdrawal. The presence or absence of a depressive state will be quantified in the forced-swim test. The current hypothesis predicts that increased severity of depressive behavior (increased immobility during the forced-swim test) during withdrawal will be positively associated with an increased rate of cocaine relapse. The specific aims include: 1) to determine the rate of acquisition for intravenous (IV) cocaine self-administration (SA) in HDS rats versus controls (Sprague-Dawley rats), 2) to determine the effect of acute IV cocaine during withdrawal on relapse rates in HDS rats versus controls, and 3) to determine the effect of an acute stress during withdrawal on relapse rates in HDS rats versus controls. The proposed studies have considerable clinical significance since their successful completion is predicted to provide insight into the role of depression in enhancing probability of relapse in cocaine-addicted patients.